Defects in the biosynthesis of thyroid hormones have been found in some paients with benign and malignant tumors of the thyroid. Alterations in the thyroid peroxidase (TPO) activity have been reported in hyperthyroid, hypothyroid, and thyroid ademona and carcinoma tissues. A systematic and precise definition of these biochemical defects has not been possible because of a lack of adequate knowledge concerning the biosynthesis of thyroid hormones. We plan to investigate, in detail, the biosynthesis of thyroid hormones in porcine tissue and to apply our biochemical findings to human studies of normal and abnormal thyroid tissue. Because TPO plays a crucial role in the biosynthesis of thyroid hormones, we plan to focus our biochemical studies on the physico-chemical, catalytic, and regulatory properties of TPO. Specifically, we propose: (1) to investigate the interaction of TPO with thyroid membranes because the hydrophobic character of TPO may in some way reflect its function in addition to its structure; (2) to purify an "intact" TPO after nonproteolytic solubilization and to compare its properties with those of fragmented, trypsin-solubilized TPO; (3) to study TPO-catalyzed iodination by comparing it with non-enzymic iodination, by use of specific modifiers of the iodination site(s), and by isolation and characterization of a TPO-associated iodinating species; and (4) to investigate the mechanism of inhibition of the iodination reaction by antithyroid drugs. Finally, an examination of abnormal human thyroid tissue will be undertaken in an effort to correlate the biochemical investigations outlined above with ongoing clinical studies of defects in the biosynthesis of thyroid hormones.